The present invention relates generally to peritoneal dialysis. More specifically, the present invention relates to manufacturing and storing bicarbonate peritoneal dialysis solutions.
The use of dialysis to support a patient whose renal function has decreased to the point where the kidneys no longer sufficiently function is known. Two principal dialysis methods are utilized: hemodialysis; and peritoneal dialysis.
In hemodialysis, the patient's blood is passed through an artificial kidney dialysis machine. A membrane in the machine acts as an artificial kidney for cleansing the blood. Because it is an extracorporeal treatment that requires special machinery, certain inherent disadvantages are present with hemodialysis.
To overcome the disadvantages associated with hemodialysis, peritoneal dialysis was developed. Peritoneal dialysis utilizes the patient's own peritoneum as a semipermeable membrane. The peritoneum is the membranous lining of the body cavity that due to the large number of blood vessels and capillaries is capable of acting as a natural semipermeable membrane.
In peritoneal dialysis, a dialysis solution is introduced into the peritoneal cavity utilizing a catheter. After a sufficient period of time, an exchange of solutes between the dialysate and the blood is achieved. Fluid removal is achieved by providing a suitable osmotic gradient from the blood to the dialysate to permit water outflow from the blood. This allows a proper acid-base, electrolyte and fluid balance to be returned to the blood. The dialysis solution is simply drained from the body cavity through the catheter.
Besides the removal of metabolism products, one of the most important problems of every kidney replacement therapy, such as hemodialysis and peritoneal dialysis, lies in the correction of metabolic acidosis. For this reason, the dialysis solutions used in each of these processes contain a buffer.
Three common buffers often used in dialysis solutions are bicarbonate, lactate, and acetate. While initially bicarbonate was the primary buffer used in dialysis solutions, over time lactate and acetate were substituted for bicarbonate. This was due to the difficulty in preparation and storage of bicarbonate-buffered dialysis solutions. Lactate and acetate buffers were found to provide greater stability in use over the previous bicarbonate-buffered solutions. See European Patent Application 90109963.0.
However, since bicarbonate ions provide advantages over acetate or lactate ions, bicarbonate is again surfacing as the primary buffer used in dialysis solutions. Tests conducted in recent years indicate patients exhibit a better tolerance for bicarbonate dialysis solutions. Further, certain treatments require sterile dialysis solutions containing bicarbonate, calcium and magnesium.
For example, one may have to dialyze a uremic patient who has developed hypotension and lactate acidosis. In such a patient, the lactate or acetate in conventional dialysates may not be metabolized to bicarbonate because of tissue hypoxia, and acidosis may be further worsened because bicarbonate is removed during dialysis. Using bicarbonate-containing dialysates in such a patient will add bicarbonate to the blood and also remove lactate. For these reasons, some researchers have recommended bicarbonate-buffered dialysis as adjunctive treatment for severe lactic acidosis. T. S. Ing. et al, Bicarbonate--Buffered Peritoneal Dialysis, The International Journal of Artificial Organs, Volume 8, No. 3, P.121 (1985).
Another potential application is with respect to patients who experience abdominal pain or discomfort when conventional acid- or lactic-buffered dialysates are infused. The abdominal pain may be related to the unphysiologically high acidity of acetate- and lactic-buffered dialysates. Conceivably, bicarbonate-buffered dialysate, with its more physiologic pH, might decrease the incidence of such symptoms. Id.
The use of medical bicarbonate solutions for injection or for dialysis treatment is known. However, due to the difficulty in preparation and storage of these solutions, a vast array of literature is dedicated to attempts to remedy the stability problem of bicarbonate solutions. Three main problems need to be addressed when manufacturing medical bicarbonate solutions.
First, in solution bicarbonate is in equilibrium with CO.sub.2 gas, which easily escapes from the solution. As a result, carbonate, a potential irritant, may form and the pH of the solution is thereby increased. To avoid these phenomena from occurring, the bicarbonate can be stored in a powder form until just before use as described in U.S. Pat. No. 4,489,535 and Jonsson et al, European Patent Application 0278100 for machine-controlled dialysis.
Alternatively, an impermeable barrier can be used to protect the solution. Or, for hemodialysis, the CO.sub.2 content of the solution can be controlled as described in Murphy et al, Use of An Artificial Kidney, J Lab. Clin. Med., Volume 40, pp. 436-444 (1952). U.S. Pat. No. 4,584,176 and European Patent No. 0,209,607 describe controlling the CO.sub.2 content of the solution. Moreover, the addition of buffers such as histidine or glycylglycine may further stabilize the bicarbonate solution. See, U.S. Pat. Nos. 5,092,838 and 4,959,175.
Second, bicarbonate solutions for injection and for dialysis generally contain calcium and/or magnesium ions. In the presence of bicarbonate, these ions form calcium carbonate and magnesium carbonate respectively, which easily precipitate from the solution, especially at a pH above 7.5. To remedy this problem, bicarbonate solutions are often made from concentrates, ranging from slightly concentrated, two-fold or less, to much more concentrated solutions. Bicarbonate on the one hand and calcium and/or magnesium on the other hand are included in separate concentrates. These concentrates are then mixed to obtain a ready to use solution. Alternatively, the concentrates are mixed and diluted.
In order to avoid the precipitation of carbonate salts, the bicarbonate concentrate is acidified when manufactured. Alternatively, the bicarbonate concentrate is mixed with an acid or acidified concentrate, either before or after dilution if dilution is needed. Acidification can be achieved with an organic (acetic acid, lactic acid), inorganic acids (hydrochloric acid) or with carbon dioxide. Ing et al., Bicarbonate--Buffered Peritoneal Dialysis, Volume 8, No. 3, p. 121 (1985). A series of machines have been proposed to assure appropriate mixing, see U.S. Pat. No. 4,489,535.
While the preparation of concentrates in separated containers initially prevents carbonate precipitation, immediate mixing of the concentrates results in carbonate precipitation. This subsequent precipitation leads to disturbances of the dialysis operation. To remedy this problem, technicians have been forced to rinse all tube lines at regular intervals with acid. Naturally, this technique results in added expense in terms of technician time and the additional cost of the acid needed.
Likewise, the dilution of the concentrated solutions to prevent carbonate precipitations has inherent disadvantages. The dilution of the solutions does not completely obviate the precipitation problem and represents an additional step. Further diluted concentrates may not adequately correct the acidosis of patients.
Third, bicarbonate solutions for injection and for certain types of dialysis need to be sterile. Either sterile filtration or steam sterilization may be used. When steam sterilization is used, many substances cannot be autoclaved together with bicarbonate. Therefore, the solution must be sterilized in at least two parts: one part containing the bicarbonate; and another part containing the incompatible substance(s), such as dextrose. In practice, two containers can be used, or alternatively, multi-compartment containers can be used. See U.S. Pat. Nos. 4,396,383 and 4,465,488.
Current procedures and preparations do not provide an adequate means to stabilize bicarbonate solutions that allow also for sterilization of such solutions. There therefore remains a need for an improved method for manufacturing and storing bicarbonate solutions.